Effect of amphetamines on blood pressure.

BACKGROUND

Daily ingestion of amphetamines is common, as they are widely prescribed for attention-deficit hyperactivity disorder (ADHD) and other diagnoses. People also use amphetamines recreationally or in an attempt to boost cognitive or athletic performance. Amphetamines have the potential to increase blood pressure, and we do not know if the long-term benefits of daily amphetamine use outweigh the potential harms.

OBJECTIVES

Primary: to quantify the changes in systolic and diastolic blood pressure in children and adults taking amphetamines, compared to placebo. Secondary: to quantify the changes in heart rate in children and adults taking amphetamines, compared to placebo; to quantify the number of withdrawals due to adverse effects of amphetamine, compared to placebo.

SEARCH METHODS

We used the Cochrane Hypertension Specialized Register, CENTRAL, MEDLINE, Embase and two clinical trial registers, together with reference checking and contact with study authors to identify the studies included in the review. We imposed no restrictions on language, publication year or publication status. The latest search date was March 2023.

SELECTION CRITERIA

Randomized controlled trials (RCTs) that compared the effects of daily oral amphetamines versus placebo on blood pressure. There were no restrictions on participants' age or gender.

DATA COLLECTION AND ANALYSIS

We used standard methods expected by Cochrane. Primary outcomes were change in systolic and diastolic blood pressure (measured in millimeters of mercury (mmHg) above atmospheric pressure; continuous outcomes). Secondary outcomes were heart rate (measured as beats per minute; continuous outcome) and withdrawals due to adverse effects (dichotomous outcome). We calculated continuous outcomes as mean differences (MD) with 95% confidence intervals (CI). We expressed withdrawals due to adverse effects as a risk ratio with 95% CI. We used a fixed-effect model to pool effect sizes from all studies.

MAIN RESULTS

We included 56 RCTs with a total of 10,583 participants, both adults and children. Most studies were conducted in North America (mainly the USA), followed by Europe. A few studies took place in Asia (Japan) and Australia. The studies tested racemic amphetamine, dextroamphetamine, mixed amphetamine salts, lisdexamfetamine dimesylate, methyl​enedioxy​methamphetamine (MDMA) and methylphenidate. The amphetamines were prescribed for ADHD, weight loss and other indications. In 48 RCTs, blood pressure was measured within 24 hours of the last dose. Based on data from all included studies, amphetamines increased systolic blood pressure (SBP) by 1.93 mmHg (95% CI 1.54 to 2.31) and diastolic blood pressure (DBP) by 1.84 mmHg (95% CI 1.51 to 2.16) (56 studies, 10,583 participants; high-certainty evidence for both). Amphetamines increased heart rate by 3.71 beats per minute (95% CI 3.27 to 4.14; 47 studies, 10,075 participants; high-certainty evidence). In a subgroup analysis limited to studies that gave participants amphetamines for at least eight weeks, the effects were similar, suggesting that these are sustained effects. These findings suggest that people taking daily oral amphetamines are at increased risk of adverse cardiovascular events. Participants in the amphetamine group were also more likely to withdraw from the study due to adverse effects compared to those given placebo (risk ratio 2.69, 95% CI 2.13 to 3.40; absolute risk increase of 4.3% over an average duration of 1 month; 42 studies, 8952 participants; high-certainty evidence). In general, the studies were well-executed, and the methodology was sound. We judged most studies to have a low risk of bias across most domains. Selection bias (random sequence generation and allocation concealment) was the domain most often rated as at unclear risk of bias, because the methods used were not reported. We judged 13 studies (23%) to have a high risk of bias in at least one of the seven domains, primarily due to high dropout rates, leading to a high risk of attrition bias.

AUTHORS' CONCLUSIONS: Daily oral amphetamines increase blood pressure, heart rate, and withdrawals due to adverse effects, with these effects observed across all time points, including shorter (≤ four weeks) and longer durations (> four weeks to < eight weeks; ≥ eight weeks) of use. Future trials should measure blood pressure using 24-hour ambulatory monitoring and assess the effect of long-term use.